Peripheral neuropathy in a mouse model lacking GBA1 in Schwann cells.

Abstract

Peripheral neuropathic symptoms have been reported in Gaucher disease (GD), a rare lysosomal storage disorder caused by mutations in β-glucocerebrosidase gene (GBA1), albeit poorly investigated only in clinical settings. To shed light on the involvement of peripheral myelination by Schwann cells (SCs) in GD, we generated a conditional knockout mouse line in which β-glucocerebrosidase is depleted in myelinating glia (Gba1f/f::cre). Adult Gba1f/f::cre peripheral nerves presented hypomyelination of large caliber axons and higher frequency of myelin infoldings, accompanied by evidence of repair-SC program activation, as indicated by the expression of p75ntr and cJun. The Gba1f/f::cre mice displayed reduced motor performance, associated with altered neuromuscular junction morphology and neuromuscular transmission. Given the well-established role of β-glucocerebrosidase in lysosomal function and autophagy, we also investigated whether its deficiency in SCs could affect nerve injury response. Despite the ability of conditional knockout mice to reach a full recovery, the initial steps of myelinophagy, a process required to eliminate myelin debris, thus prompting axon regeneration, were impaired in β-glucocerebrosidase deficient SCs in vivo. Consistently, when in vitro nerve degeneration was induced in presence of the β-glucocerebrosidase inhibitor conduritol B epoxide (CBE), a block in the autophagic flux was observed. Our data show that decreased degradation efficiency and/or accumulation of bioactive lipids in SCs lacking β-glucocerebrosidase sustain the activation of a repair-SC program, leading to myelin and axonal defects. These results indicate a novel role for GBA1 in guaranteeing SC lysosomal function as relevant for peripheral nerve homeostasis.